Severe asthma is a complex heterogeneous disease with significant health care utilization, poor quality of life and increased mortality. Our understanding of the disease pathobiology has significantly advanced, particularly through the NHLBI Severe Asthma Research Program (SARP). Through multivariate cluster analyses using objective physiologic and biologic parameters, unbiased phenotypic analyses divides the spectrum of asthma into subpopulations with specific disease characteristics that strongly suggest variability in therapeutic responses to corticosteroid and additional controller therapies. This heterogeneity is particularly apparent among asthmatic patients with more severe disease. This approach, based on understanding disease pathobiology, has greater personalized therapeutic implications than an approach which just broadly classifies severe asthma as asthma that is not adequately controlled using corticosteroids and additional controllers. This proposal represents an extension of the understanding gained in SARP, where we will define therapeutic responses across a spectrum of severe asthma to further define phenotypes/endotypes using known biomarkers while developing and testing novel molecular and genomic biomarkers. While the understanding of severe asthma phenotype/endotype pathobiology has advanced, the response to therapies which target specific inflammatory pathways in asthma is not completely understood. Furthermore, we are not able to definitively predict response to treatments based upon a priori clinical characteristics and expression of known biomarkers. To advance precision medicine approaches in severe asthma, it is crucial to understand the phenotypes and endotypes including cellular, protein and genomic biomarkers that predict asthma pharmacologic responsiveness to specific asthma interventions. We hypothesize that adaptive sequential clinical trials are an important fundamental approach to address asthma heterogeneity and to make major advances in the treatment of severe asthma. To test this hypothesis, we will perform clinical and molecular phenotyping in participants with severe and/or exacerbation prone asthma to include responsiveness to corticosteroids to identify specific phenotypes/endotypes for participation in a network wide PrecISE trial. (Aim 1). In Aim 2, we will collaborate with all other clinical sites to perform innovative, sequential adaptive clinical trials including novel interventions based on predictive biomarkers. In Aim 3, we will refine current biomarkers and develop new predictive and dynamic biomarkers of response before and after treatment with targeted therapies to increase their predictive abilities and introduce new biomarkers to the clinical arena. This proposal will allow patients with severe asthma access to novel therapies and improve our ability to predict therapeutic responses using clinical and molecular biomarkers in this heterogeneous disease.